The overall goal of this project is to develop 18F PET radioligands for molecular targets that are implicated in the pathophysiology of brain and behavioral disorders (e.g. receptors, intracellular messengers, and disease related proteins). Our immediate goal is to synthesize and biologically characterize an 18F-labeled dopamine D2 agonist radioligand that will ultimately be used for the in vivo evaluation of the role of changes n D2 receptor status in several neurological disorders such as schizophrenia. The D2 receptor has been shown to exist in two states, D2high and D2low. Dopamine supersensitivity, which is marked by an increase in the percentage of D2 receptors in the high state, is implicated in neurological disorders such as schizophrenia and Parkinson's disease, among others. Existing [D2/3] radiotracers, such as [11C] raclopride or [18F] fallypride, are D2 antagonists and show equal affinity for D2high and D2low, and cannot, therefore be used to assess increases in D2high. In contrast, D2 agonists show a higher affinity for D2high than for D2low and can, therefore, is used to measure these differences in vivo. At the present time, however, there are no [suitable] 18F-labeled D2 agonist radioligands available. The goal of this project is to develop such compounds. We have identified MCL-524 as a promising starting point for the development of this radioligand. Preliminary in vitro studies carried out in our laboratories showed that the nonradioactive compound is, in fact, a D2 agonist and that MCL-524 can be radiolabeled with 18F. The objective of this project is to extend these very promising preliminary results, laying the groundwork for future human evaluation of this compound. This objective forms the basis for the hypothesis that will be tested: An 18F-labeled D2 agonist radioligand can be used to assess the changes in D2 receptor status that characterize D2-related neurological diseases such as schizophrenia and Parkinson's disease. Fulfillment of this objective will provide a solid basis for advancing the best 18F PET D2 agonist radioligand into humans. Such a radioligand, if developed, would allow a way to study D2 receptor dynamics in relation to the DA system as well as other neurotransmitter systems, and thus allow us to advance our understanding of different neurological disorders.